This invention relates to a method to enhance an immune response of nucleic acid vaccination by simultaneous administration of a polynucleotide and a polypeptide of interest.
In 1990 Wolff and colleagues (Wolff et al., Science 247:1465-1468 (1990)) reported that nonreplicating plasmid DNA encoding reporter genes could be internalized by muscle cells, without the use of any transfection vehicle, and that the encoded proteins were expressed following injection of the plasmid DNA. The subsequent finding that the expressed protein of xe2x80x9cnakedxe2x80x9d (i.e., devoid of agents which promote transfection) plasmid DNA was immunogenic upon intramuscular inoculation has opened a new area of research with significant clinical impact.
As such, vaccination with nucleic acids (NAVAC) has become a relatively new approach for vaccinating against a multitude of diseases. It involves the in vivo production of a polypeptide within a host cell rather than the more conventional method of administering a polypeptide (or an attenuated, or killed microorganism) that was first produced (or cultured) in vitro. NAVAC also differs from more conventional vaccines in that the compound administered consists of nucleic acids, i.e., DNA or RNA, encoding selected antigen(s). Upon injection of these nucleic acids, they are taken up by the recipient cells of a mammalian host and the antigen encoded by such nucleic acid(s) is subsequently expressed. Thereafter, the presence of a foreign antigen within a host can elicit a specific immune response directed against the antigen. It has been shown that NAVAC induces humoral, i.e., antibodies, as well as cell mediated immunity, i.e., T helper cell responses and cytotoxic lymphocytes (see, e.g., Corr et al., J. Exp. Med. 184:1555-1560 (1996); Doe et al., Proc. Nail. Acad. Sci. 93:8578-8583 (1996)).
The induced immune responses have been shown to protect against a subsequent challenge with the infectious organism from which the antigen was originally obtained in a certain number of animal models (e.g. Ulmer et al., Science 59:1745-1749(1993); Sedegah et al., Proc Natl Acad Sci USA 91:9866-9870 (1994); Manickan et al., J. Inmmunol. 155:259-265 (1995)). NAVAC has been shown to be much less efficient in larger animal species (when compared to administration of adjuvanted proteins), and large amounts of DNA have to be administered to achieve immunisation levels comparable to that found in smaller animal species, e.g., mice (Gramzinski et al., Vaccine Research 5:173-183 (1996); Lu et al., J. Virol. 70:3978-3991 (1996); Shiver et al.; Joumal of Pharmaceutical Sciences 85:1317-1324 (1996)). There is thus a need to improve the efficacy of NAVAC, for example, by developing new delivery and targeting mechanisms, new adjuvantation techniques, other routes of administration, etc. It is the object of this invention to provide another improvement to the efficacy of DNA vaccination.
In one aspect, the present invention provides a method for enhancing the immune response of a nucleic acid vaccination by administration of (i) a polynucleotide encoding a gene of interest, which encodes a polypeptide and (ii) by also administering the polypeptide simultaneously, that is, during the same ongoing immune response. Preferably the administration of polynucleotide and polypeptide occur within 0-10 days of each other. One preferred embodiment is administration of polypeptide 3-7 days prior to administration of polynucleotide. The polypeptide may be further prepared prior to administration such that it is presented to the immune system in such a way to provide a delayed release (e.g., encapsulated). In such a case, the polypeptide is preferably administered at the same time (concurrently) as the polynucleotide.
In another aspect, the present invention provides a method for enhancing the immune response of a polypeptide vaccination by administration of a nucleotide encoding a gene of interest, which encodes a polypeptide of interest, and by also administering the polypeptide simultaneously, that is, during the same ongoing immune response.
In further related aspects, the present invention relates to pharmaceutical compositions, vaccines, and methods to prepare such compositions and vaccines, comprising a polynucleotide encoding a gene of interest, and the corresponding polypeptide of interest, where the ratio of polynucleotide to polypeptide is from 1000:1 to 1:1 (w/w). Optionally, the polypeptide is prepared prior to administration such that it is presented to the immune system in such a way to provide a delayed release.